Distinct molecular pathways mediate Mycn and Myc-regulated miR-17-92 microRNA action in Feingold syndrome mouse models

• Published in: Nature communications Vol. 9; no. 1; pp. 1352 - 10
• Main Authors: Mirzamohammadi, Fatemeh, Kozlova, Anastasia, Papaioannou, Garyfallia, Paltrinieri, Elena, Ayturk, Ugur M., Kobayashi, Tatsuya
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 10.04.2018; Nature Publishing Group; Nature Portfolio
• Subjects: 1-Phosphatidylinositol 3-kinase; 13/51; 38/39; 631/337/384/331; 631/45/127/1219; 64/110; 692/699/1670/1669; 96/1; Animal models; Animals; Bone dysplasia; Disease Models, Animal; Eyelids - abnormalities; Eyelids - metabolism; Eyelids - pathology; Female; Gene Expression Regulation; Heterozygosity; Heterozygote; Humanities and Social Sciences; Humans; Inhibition; Intellectual Disability - genetics; Intellectual Disability - metabolism; Intellectual Disability - pathology; Kinases; Limb Deformities, Congenital - genetics; Limb Deformities, Congenital - metabolism; Limb Deformities, Congenital - pathology; Male; Mesenchyme; Mice; Mice, Knockout; Microcephaly - genetics; Microcephaly - metabolism; Microcephaly - pathology; MicroRNAs - genetics; MicroRNAs - metabolism; miRNA; Molecular modelling; multidisciplinary; Mutation; Myc protein; N-Myc Proto-Oncogene Protein - deficiency; N-Myc Proto-Oncogene Protein - genetics; Pharmacology; Phenotypes; PTEN Phosphohydrolase - genetics; PTEN Phosphohydrolase - metabolism; PTEN protein; Ribonucleic acid; RNA; Science; Science (multidisciplinary); Signal Transduction - genetics; Signaling; Skeleton; STAT3 Transcription Factor - genetics; STAT3 Transcription Factor - metabolism; Tracheoesophageal Fistula - genetics; Tracheoesophageal Fistula - metabolism; Tracheoesophageal Fistula - pathology; Transcription factors; Transforming Growth Factor beta1 - genetics; Transforming Growth Factor beta1 - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-03788-7

Feingold syndrome is a skeletal dysplasia caused by loss-of-function mutations of either MYCN (type 1) or MIR17HG that encodes miR-17-92 microRNAs (type 2). Since miR-17-92 expression is transcriptionally regulated by MYC transcription factors, it has been postulated that Feingold syndrome type 1 and 2 may be caused by a common molecular mechanism. Here we show that Mir17-92 deficiency upregulates TGF-β signaling, whereas Mycn -deficiency downregulates PI3K signaling in limb mesenchymal cells. Genetic or pharmacological inhibition of TGF-β signaling efficiently rescues the skeletal defects caused by Mir17-92 deficiency, suggesting that upregulation of TGF-β signaling is responsible for the skeletal defect of Feingold syndrome type 2. By contrast, the skeletal phenotype of Mycn -deficiency is partially rescued by Pten heterozygosity, but not by TGF-β inhibition. These results strongly suggest that despite the phenotypical similarity, distinct molecular mechanisms underlie the pathoetiology for Feingold syndrome type 1 and 2. Feingold syndrome is a skeletal dysplasia caused by mutations in MYCN or MIR17HG, but it is not clear if these mutations lead to pathology via a common molecular mechanism. Here, the authors show that mutations in MIR17HG lead to upregulated TGF-β signaling in limb mesenchymal cells, while mutations in MYCN downregulate PI3K signaling.